Project Summary/Abstract Practice effects and ceiling effects could result in type 1 or type 2 errors in clinical trials involving early stage AD populations, given the necessity of serial assessments. Our funded parent grant (1R01AG051346) has the overarching goal of validating novel cognitive and everyday functional measures that have sharply attenuated practice effects and are not prone to ceiling effects for use in preclinical Alzheimer's disease (AD) trials in which participants are cognitively within normal limits. To implement this, we are conducting an innovative parallel group study in which 320 healthy, non-cognitively impaired older subjects are randomized to one of two groups based on assessment type (novel vs. established instruments) and receive three serial assessments over a one-year period. We will employ this parallel group design in order to maintain the structure of a clinical trial, while pari passu, highlighting contrasts between novel and established measures and completely avoiding any interference effects between them. Our novel cognitive measures include tests of executive function, episodic memory, and processing speed combined into a single composite. Our functional measures involve computerized performance based, ecologically relevant instrumental activities. We will compare our novel No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment System (CFAS) against established measures that include the PACC, ADAS-Cog, and FAQ. Our Revision (Competing Supplement) will further test the sensitivity of the novel measures to: 1. hippocampal atrophy and cortical thinning over a one-year interval by adding an additional MR scan at the one-year endpoint of the study; and 2. Collection of additional Blood-based (BB) biomarkers at baseline and endpoint that include total-tau, and Nfl. These are related to AD pathology and in the case of Neurofilament light chain (Nfl), to neuroaxonal injury. As such these new measures should provide convergent data as to the utility of the new measures. Additionally, we will also compare the sensitivity of the novel measures to the established measures with respect to the additional data collected in this expansion of the study. We are requesting funding for the final three years of our parent R01. Thus, in AIM 1. We will assess the relationship between change from baseline to endpoint in MR measures and change in novel and established cognitive and functional measures. We predict that the change score in novel measures will be more highly associated with change in MR measures than established measures. AIM 2. A. We will assess the relationship between changes in BB biomarkers total tau and Nfl, measured at baseline and endpoint and changes in novel and established cognitive and functional measures. B. We will assess the ability of the biomarkers to predict cognitive decline. We predict that for A. and B. associations will be more robust in the novel measures group.